1. Field of the Invention
The present invention relates to biologically protected peptidyl prodrugs generally useful in the treatment of proliferative disorders and other illnesses. These prodrugs represent a novel form of drug delivery that extends the biologically active life of many therapeutic formulations. The present invention also relates to methods of making and using these prodrugs.
2. Background of the Invention
Many therapeutic agents are limited in their use because they have an abbreviated pharmacological life. The pharmacological effect of a drug is related to the drug concentration at its site of action and the duration of drug exposure. There is a further relationship between the concentration of a drug at its site of action and the drug concentration in the systemic circulation. Drugs that can quickly metabolize or become inactivated are rapidly removed from the system circulation and therefore often require high doses and/or frequent administration to achieve effective systemic levels and the desired pharmacological activity in the body. High doses of drugs and frequent drug treatments can be costly, dangerous and impractical. Sustained-release pharmaceutical preparations reduce these problems while affording equivalent biological activity.
The present invention is generally directed to various prodrugs useful in the treatment of, among other illnesses, leukemia. The term "prodrug" as used herein, and as will be understood by one skilled in the art, refers to a biologically inactive chemical compound that is converted into a biologically active agent within the body. The prodrugs of the present invention lack pharmacological activity until they are spontaneously activated in the body to form biologically active drug forms. The activated prodrugs of the present invention generally show the same efficacy in the body as the parent compounds, but provide the added advantage of having a longer active life within the body.
The prodrug concept is of particular interest for those drugs that undergo rapid metabolism in the body. An example of one such drug is ara-C, which is also known by the names cytosine arabinoside, cytarabine and 1-(.beta.-D-arabinofuranosyl) cytosine. Ara-C is known to be an important and effective antimetabolite for use in the therapy of acute non-lymphocytic leukemia in adults and children, acute lymphocytic leukemia and the blast phase of chronic myelocytic leukemia. It is also used in the prophylaxis and treatment of meningeal leukemia and for non-Hodgkin lymphoma in both adults and children.
Ara-C is an analogue of the pyrimidine nucleosides cytidine and deoxycytidine, with an arabinose sugar moiety replacing ribose or deoxyribose. Ara-C kills cells in the DNA synthetic phase (S-phase) of the cycle by an active process called apoptosis, and functions by inhibiting DNA polymerase, the enzyme that catalyzes the formation of DNA. To function in this capacity, the drug must be activated by pyrimidine nucleoside kinases that first promote formation of the nucleotide ara-cytosine monophosphate (ara-CMP) and then convert ara-CMP to the diphosphate and triphosphate nucleotides ara-cytosine diphosphate (ara-CDP) and ara-cytosine triphosphate (ara-CTP). Accumulation of ara-CTP causes potent inhibition of DNA synthesis in many cells. Inhibition of DNA chain elongation is effected when ara-C is incorporated at the terminal position of a growing DNA chain. There is also evidence that ara-C incorporated into DNA slows DNA template function. Cell death occurs when ara-C causes continuous inhibition of DNA synthesis for a duration of at least one cell cycle, so that cells are exposed in the S-phase. The mean cell cycle time in human acute myelocytic leukemia is one to two days.
Accumulation of sufficient ara-CTP to effectively inhibit DNA synthesis is impeded by the action of two enzymes--cytidine deaminase and dCMP deaminase. Ara-C is rapidly metabolized in the body by cytidine deaminase to form the nontoxic metabolite arauridine (ara-U); cytosine deaminase cleaves the primary amine from ara-C thereby rendering the drug inactive. In addition, dCMP deaminase converts ara-CMP to the inactive metabolite uracil arabinoside (ara-UMP). About 80% of a given ara-C does is excreted in the urine within 24 hours, with less that 10% appearing as cytarabine; the remainder is ara-U. Accordingly, the drug must be administered by continuous infusion that requires hospitalization or frequent administration of high doses that are sometimes associated with significant untoward effects.
Use of ara-C, and derivatives thereof, in the treatment of various illnesses is known in the art. For example, U.S. Pat. Nos. 3,991,045, 4,055,716 and 4,097,665 disclose N.sup.4 -acyl-1-.beta.-D-arabinofuranosylcytosine, N.sup.4 -acyl-1-.beta.-D-arabinofuranosylcytosine-5'-esters and diacylnucleosides, respectively, useful as chemotherapeutic agents in the treatment of cancer. U.S. Pat. No. 4,145,414 discloses 5'-esters of aracytadine, and methods of making the same, which show sustained release of ara-C in the body. U.S. Pat. No. 4,367,332 discloses N.sup.4 -alkoxycarbonylarabinofuranosyl cytosine compounds generally useful as anti-tumor agents.
None of the above patents teach or suggest the prodrugs, or methods of making and using the same, taught by the present invention. Accordingly, there remains a very real and substantial need to provide drugs which have a longer pharmacologically active life in the body. The present invention addresses this need.